Note: Descriptions are shown in the official language in which they were submitted.
~30 1 40639 CAN 4~
F.N. 40639 US~ 3
PROCESS FOR 6,7-DIHYDRO-5,8-DIMETEIYL-9-FLUORO-
1-OXO-lH,5~1-BENZO[i,j]QUINOLIZINE-2-CARsOXYLIC ~CID
This invention relates to the synthesis of
benzo[i,j]quinolizines substituted at the 8-position by a
methyl group. More specifically it relates to a synthetic
process for 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-lH,5H-
benzo[i,j]quinolizine-2-carboxylic acid. This invention
further relates to certain individual steps of the process
and to a novel synthetic intermediate prepared by one such
step.
United States Patent 4,472,405 describes the
synthesis of 6,7-dihydro-5,8-climethyl-9-fluoro-1-oxo-
1~1,5H-benzo[i,jlquinolizine-2-carboxylic acid. The
synthetic procedure disclosed in tllat patent utilizes
5-amino-2-fluorobenzoic acid as a starting material to
provide 6-fluoro-5-methyl-1l2,3,4-tetrahydroquinaldine and
requires two reduction reactions to ohtain the intermediate
6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine ~rom
6-fluoro-5-carboxyc~uinaldine. rhese reduction reactions
result in a reduced yield over~ll, and thus an alternate,
more efficient synthesis was desired. The process of
Example 1 of the invention provides a higher yield of
6~7-dihydro-5~8-dimethyl-9-fluoro-l-oxo-lH~5H-benzo[ij~-
quinolizine-2-carboxylic acid than the process described in
U.S. Patent no. 4,472,405.
United States Patent No. 4,301,289 describes the
compounds 6-fluoro-2-methylquinoline, 6-~luoro-2-methyl-
1,2,3,4-tetrahydroquinoline, and ~dialkyl 2-[N-(6-fluoro-2-
methyl-1,2,3,4-tetrahydroquinolinyl)~methylenemalonates.
United States Patent No. 4,472,407 describes the compound
5-bromo-6-fluoro-2-methylquinoline and lts synthesis.
Kohei Tamao et al., Bulletin Chemical Society of
Japan, 49, 195~-1969 (19751, describes nickel-catalyæed
~'
~3~4~3
-2-
Grignard displ~cements of certain aromatic halides~
Dichlorol1,3~bis(diphenylphospllino)propane) nickel (II)
catalyst is specifically disclosed. Bergstrom et al.,
Tetrahedron Letters, 23, 4191-4194 (1982), discloses the
synthesis of ~-alkyl and 6-aryl substituted
9-~-D-ribofuranosyl purines via the nickel catalyzed
coupling of Grignard reagents to 2~,3~,5~-tris-o-(t-butyl-
dimethylsilyl)-9-~-D-ribofuranosyl-6-chloropurine.
~ichlorol1,3-bis(diphenylphosphino)propanel nickel ~II)
catalyst is again specifically disclosed.
The present invention provides a process for the
preparation of 6,7-dihydro-5,8-dimethyl-g-fluoro-1-oxo-
lH, 5H-benzo[i,j~quinolizine-2-carboxylic acid of Formula I:
o
C113
~ ~ l
\CH3
the process comprising:
1) reacting 6-fluoro-2-methylquinoline (II) with
bromine in the presence of a strong Lewis acid to
provide 5-bromo-6-fluoro-2-methylquinoline (III):
2) reacting the quinoline of formula III with
a methyl Grignard in the presence of dichloro[1,3-
bis(diphenylphosphino)propanel nickel (II) to provide
2,5-dimethyl-6-fluoroquinoline (IV);
3) reducing the compound of Formula IV in the
presence of a catalyst to provide 2,5-dimethyl-6-
fluoro-1,2,3,4-tetrahydroquinoline (V);
4) condensing the tetrahydroquinoline of Formula
V with a diester of an alkoxymethylenemalonic acid of
Formula VA (wherein "alk" is an alkyl group containing
1 to about 4 carbon atoms and each R' is independently
an alkyl group containing 1 to about 4 carbon atoms or
~3C1~:4~3
the R's together form an isopropyl radical) to provide
a diester of (2,5-dimethyl-6-fluoro-l,2,3,4-tetra-
hydro-l-quinolinyl)methylenemalonic acid (VI);
5) cyclizing the compound of Formula VI to
provide the ester of 6,7-di11ydro-5,8-dimethyl-g-
fluoro-l-oxo-lH,511-benzo~i,j]quinolizine-2-carboxylic
acid (VII), and
6) hydrolyzing the compound of Formula VII to
give 6,7-dihydro-5,8-dimethyl-9-fluoro-l-oxo-l11,5H-
benzo[i,j~quinolizine-2-carboxylic acid (I).
This invention also relates to processes
comprising the reaction of step (2) and, optionally, the
reaction of step (3) above.
This invention further relates to the novel
intermediate 2,5-dimethyl-6-fluoroquinoline, the product of
step ~2) above.
More particularly, in one embodiment, the process
of the invention is illustrated in the Reaction Scheme
below, wherein alk and R' are as defined above:
'
:
: :
~302~L~3
Br
F~ ~ Br2 Al~ > Y` ~X~
I I C113 CE~3
( 2 ) ¦ CH3MgX
CH3 C~3 1~
10 F~ <~ Y CN3 IV
V
/CO2R'
4 ) a 1 k-O-CElaC\ V~
. ~ C02R
CH
R~O C ¦ 3 > CN~<O2R' Vll
/C ~ C--H CH3
R' 02C
VI ( 6 ) ~/
3 0 F~ C02N
CH3
~3C~2~1L3
--5--
In the first step of the Reaction Scheme the
known compound 6--fluoro-2-methylquinoline (II) is reacted
with bromine in the presence of a strong Lewis acid such as
aluminum chloride at an elevated temperature such as
50-80C. The Lewis acid is preferably employed in a ratio
of about 1.5 equivalent of the Lewis acid per mole of the
quinoline. The reaction may be run neat or i~ a suitable
inert solvent such as 1,2-dichloroethane, chloroform or
methylene chloride. It is presently preferred to use a
slight, for example, 10%, excess of bromine, but an
equimolar amount may also be used if desired. When the
reaction is complete, the product may be isolated as a zinc
complex which is then freed by addition of a strong base
such as ammonium hydroxide. The product of step (1) is
5-bromo-6-fluoroquinaldine ~Formula III), a known compound.
Step (2) of the Reaction Scheme requires reacting
the 5-bromo-6-fluoroquinaldine (Formula III) with a methyl
Grignard reagent in the presence of
dichloro[l,3-bis(diphenylphosphino)propane~ nickel (II)
catalyst. The reaction is run in a solvent such as diethyl
ether or toluene at a temperatllre preferably between 5C
and 20C. The Grignard counterion may be bromide or
chloride, but chloride is presently preferred. Also, 1.2
to 1.4 equivalents of Grignard may be used, and the nickel
catalyst is used in a range of 0.01 to 0.10 equivalents
with 0.05 being preferred. The progress of the reaction
may be monitored by gas chromatography. When the reaction
is complete, the product, which is novel
2,5-dimethyl-6-fluoroquinoline, is extracted into dilute
acid, for example, dilute hydrochloric acid and is then
precipitated by addition of a base, for example, ammonium
hydroxide.
In step (3), the quinoline of Formula IV is
reduced to the tetrahydroquinoline of Formula V. The
catalysts for this reaction are platinum-based, for example
platinum on charcoal, about 0.3g to l.Og of catalyst per
20g of quinoline being used. The compound of Formula IV is
iL3~24~3
-6-
dissolved either in a weak organic acid such as acetic, or
in a mixture of a lower alkanol ~i.e., one containing one
to five carbon atoms) such as isopropanol and a weak
organic acid. The mixture is hydroqenated at a pressure of
30 to 60 psi at a temperature of preferably about 20C.
~fter completion of the reduction reaction the catalyst is
removed by filtration and the solvent is evaporated. The
residual solid is taken up in an organic solvent such as
toluene or 1,2-dichloroethane. The organic solution is
washed with base, dried and evaporated to give the product
of Formula V.
The 2,5-dimethyl-6-fluoro-1,2,3,4-tetrahydro-
quinoline of Formula v is condensed with a diester of an
allcoxymethylenemalonic acid (VA) in step (4). The
preferred diester of Formula V~ is diethyl ethoxy-
methylenemalonate since it is most readily available.
Other suitable diesters of alkox~methylenemalonic acid
include cycloisopropylidenyl alkoxymalonates of the formula
O~ ~ O
Alk OCH-C ~ CH3
O~ O C~l3
wherein alk is as defined above.
The condensation reaction requires heating the
reactants until the reaction is complete as determined by
gas chromatography. The reaction is conducted in the
absence of solvent at a temperature of 100-200C and
preferably 140-160C. The alcohol by-product is preferably
removed by distillation to drive the reaction to
completion. The product of this reaction is the compound
of Formula VI. It may be isolated or may be used directly
in step (5) without isolation.
In step (5) the intermediate of Formula VI is
cyclized to form the intermediate ester of Formula VII.
The cyclization step is preferably carried out by heating
:~3~2413
--7--
the intermediate of ~ormula VI in the presence of
phosphorus oxychloride. The reaction may be carried out
neat or in ~ suitable solvent such as toluene. Excess
phosphorus oxychloride is destroyed by the addition of
either base or ethanol. ~lternatively, the cyclization
reaction may be carried out by heating the intermediate of
Formula VI in the presence of polyphosphoric acid. The
isolated product may be used directly in step (6), or it
may be purified by recrystallization before using it in
step (6).
The ester of Formula VII is saponified in step
(6) by conventional means such as hydrolysis in hydro-
chloric acid to provide 6,7-dihydro-5,8-dimethyl-9-
fluoro-1-oxo-lH,5H-benzo[i,j~quinolizine-2-carboxylic acid
of Formula I.
Step (6) need not be conducted if step (5) is
conducted using polyphosphoric acid since the ester would
then be saponified in step (S).
The Eollowing examples are provided to illustrate
the invention and are not intended to be limiting oE the
invention. ~11 amounts expressed are by weight unless
otherwise indicated.
EXAMPLE 1
Part A. Pre aration of 5-Bromo-6-fluoro-2-methylquinoline
P
A solution of 20.13g (0.125 mole) of 6-fluoro-2-
methylquinoline in 25 ml of 1,2-dichloroethane was added
slowly to a mixture of 25.3g (0.189 mole) of aluminum
chloride and 25 ml of 1,2-dichloroethane. The resulting
solution was heated to 70C-80C, and 19.9Bg (0.125 mole)
of bromine was added dropwise thereto. The reaction
mixture was heated at 80C-85C for about 16 hours and was
poured onto ice and acidified by adding 100 ml concentrated
hydrochloric acid. 17O04g (0.125 mole) of zinc chloride
was added, and the resulting suspension was heated on a
steam bath for 15 minutes. After cooling in an ice bath
the complex was collected by filtration and washed
~30Z~
sequentially with 100 ml of cold 3N hydrochloric acid and
100 ml oE methylene chloride. The complex was slurried ln
100 ml of waterj and the pH was adjusted to pH 11 with
ammonium hydroxide. The product was collected by
filtration, washed with water and dissolved in 150 ml of
toluene. The toluene solution was treated with magnesium
sulfate and decolorizing charcoal, and was then evaporated
to give 22.5g (0.094 mole) of 5-bromo-6-fluoro-2-methyl-
quinoline, a known compound. The structural assignment was
confirmed by nuclear magnetic resonance spectral analysis.
Part ~ rnthesis of 2,5-Dimethyl-6-fluoroquinoline
Under a nitrogen atmosphere, 28.0g ~0.05 mole) of
dichloroll,3-bis(diphenylphosphino)propane] nickel~ II )
cata]yst (prepared by the method of G. R. Van ~lecke and W.
DeW. Horrocks, Inorganlc Chemis~ry, 5, 1968 (1966),
incorporated herein by reference~ was added to a solution
of 240g (1.0 mole) o 5-bromo-6-fluoro~2-methylquinoline in
3.8 liters of toluene. 440ml (1.4 mole) of 3.17 molar
methylmagnesium chloride in tetrahydrofuran was added
rapidly to the above mixture, the resulting exotherm being
controlled with an ice bath. The reaction was allowed to
stir at room temperature overnight. ~he reaction was
treated with 1 liter of water to destroy the excess
Grignard reagent, and the organic layer ànd aqueous layers
were then separated. The organic layer was extracted twice
with 1 liter portions of 3N hydrochloric acid. The acid
extracts were combined, extracted twice with 1 liter
portions of methylene chloride, and made basic (pH>9) with
ammonium hydroxide and ice. The product was collected as a
tan solid (156.4g, O.B94 mole). This material was
recrystallized from 1 liter of hexane to give 77.1g ~0.44
mole) of 2,5-dimethyl-6-fluoroquinoline which was 98.7%
pure as determined by gas chromatographic analysis.
9 ~3~
Part C. Pre ~ ,5-Dimethyl-6-fluoro-1,2,3,4-
y~oq~inoline
7.Okg of 2,5-dimethyl-6-fluoroquinoline, 51.5kg
of glacial acetic acid and 350g of 50% water-wet 5%
platinum on carbon catalyst were combined and hydrogenated
at 50 psi for 20 hours. Gas chromatography showed residual
starting material so an additional 35g of catalyst was
added and the hydrogenation was continued or an additional
2 hours. The mixture was filtered to remove the catalyst
and the solvent was then evaporated. The residue was
dissolved in 10 gallons of cold water, and the resulting
mixture was made basic with ammonium hydroxide to pH 11
while maintaining the temperature below 30C. The
resulting mixture was extracted with 8 gallons of
1,2-dichloroethane and the extract was dried througn
azeotropic distillation. ~rhe dried extract was treated
with magnesium sulfate and filtered, and the filtrate was
concentrated in vacuo to give a dark oil, 2,5-dimethyl-6-
fluoro-1,2,3,4-tetrahydroquinoline, which was used dlrectly
in the next step.
Part D . Preparation of Diethyl (2,5-dimethyl-6-fluoro-
1,2,3,4-tetrahydro-1-quinolinyl~methylenemalonate
3350 g ~18.7 mole) of 2,5-dimethyl-6-fluoro-1,2,-
3,4-tetrahydroquinoline and 4445.7 g (20.6 mole) of
diethyl ethoxymethylenemalonate were combined and heated to
110C. The ethanol was removed by atmospheric distillation
initially and then through vacuum distillation when the
reaction temperature reached 150~C. The resulting
material, diethyl (2,5-dimethyl-6-fluoro-1,2,3,4-tetra-
hydro-l-quinolinyl)methylenemalonate, was used directly in
the next step.
Part E.
fluoro-1-oxo-lH,5H-be
carboxvlate
..
A solution of 36.6 mole of diethyl ~2,5-dimethyl-
6-Eluoro-1,2,3,4-tetrahydro-1-quinolinyl)methylenemalonate
~L3~ 3
--10--
in 8.Okg of toluene was added over a period of two hours to
40 kg of refluxing phosphorus oxychloride. Reflux was
maintained during the addition and for 1.5 hours after the
addition had been completed. The reaction was monitored by
gas chromatograplly. The solvent was evaporated under
vacuum. The residue was mixed with 50 kg of cold
l,2-dichloroethane, and a solution of 9.5kg of sodium
hydroxide in 45.5kg of water was added while maintaining
the temperature below 35C. The organic and aqueous phases
were separated and the aqueous layer was extracted with
l,2-dichloroethane. The two organic extracts were
combined, dried through azeotropic distillation, and
concentrated _n vacuo to give a dark solid. This solid was
dissolved in 38 kg of denatured ethyl alcohol, filtered to
lS remove insoluble salts and coolecl to lOCC. The resulting
solid was collected, reslurried with 5 gallons of cold
ethanol, and collected and c1ried to give 68g2g of ethyl
6,7-dihydro-5,8 dimethyl-9-fluoro-l-oxo-lH,511-benzo~
quinolizine-2-carhoxylate. A second crop of 1596g was
obtalned by concentrating and cooling the mother liquors.
Part F. Preparation of 6,7-Dihydro-S,~-dimethyl-9-fluoro-
l-oxo lH_5E~-benzo[l,~]quinolizine-2-carbox~lic
Acid
5.80kg (l9.l mole) of the ethyl ester from Part E
was added to 58kg of 5% aqueous sodium hydroxide. The
mixture was heated to 85C over a period of one hour and
was then maintained at 85C for 0.5 hour. The solution was
filtered and then added to a mixture of l8kg of 30~ aqueous
hydrochloric acid and 5 gallons of crushed ice. The
temperature was kept below 10C. The resulting solid was
collected, rinsed with lO gallons of water, resIurried with
12 gallons of water, recollected and rinsed with 2 gallons
of water. The solid was dried under vacuum at 90C to give
5010g of 6,7-dihydro-5,8-dimethyl-9-fluoro-l-oxo-lH,5H-
benzo[i,jlquinolizine-2-carboxylic acid.
~3~Z~3
-Ll-
_X~MPL~ _
Preparation of S-Bromo-6-fluoro-2-methyl~uinoline
.
20.1 g (0.125 mole) of 6-fluoro-2-methylquinoline
was added to 25.3g (0.189 mole) of aluminum chloride at a
temperature of 60C. 19.98g (0~125 mole) of bromine was
added as a gas. The reaction mixture was heated overnight
at ~0C. The reaction mixture was then poured onto ice,
and 50% aqueous sodium hydroxide was added until the bulk
of the solids had dissolved. The mixture was then
extracted with toluene. The toluene extract was dried with
magnesium sulfate and evaporated under vacuum to give 23g
of 5-bromo-6-fluoro-2-methylquinoline as a light tan solid.
The structure was confirmed by nuclear magnetic resonance
spectral analysis.
EXAMPLE 3
.
Preparation of 5-Bromo-6~fluoro-2-methylquinoline
~ solution of 12.1 kg (75 mole) of 6-fluoro-2-
methylquinoline in 33 liters of 1,2-dichloroethane was
chilled to 5C, and 15.0 kg (113 mole) of aluminum chloride
was added thereto in portions over 15 minutes. The mixture
was purged with nitrogen and then heated to 75C. A
solution of 13.2kg (82.6 mole) of bromine in 2 liters of
1,2-dichloroethane was added over a period of 5.5 hours.
The reaction was maintained at 75C during the addition and
for an additional 15 minutes after the addition was
co~pleted. The reaction was stirred at 70C for 23 hours
and was then cooled to 10C and slowly added to a mixture
of 8 kg of 30% hydrochloric acid, 41 liters of water and
31.75 kg of ice. The mixture warmed to 50C during the
addition. The mixture was heated to reflux and the
1,2-dichloroethane was removed by azeotropic distillation.
The remaining aqueous solution was cooled to 60C and 12 kg
of 10% hydrochloric acid was added. The solution was
treated with Celite~ (available from Johns-Manville Corp.)
and filtered. The filtrate was cooled to 25C and 18 kg of
30~ hydrochloric acid and 1~.22kg of zinc chloride were
~3~2~L3
-12-
added. The resulting slurry was chilled to 5C and allowed
to stir for several days. The solid was collected and then
reslurried with 10 gallons of water. The slurry was
chilled to 5C and 22 kg of chilled ammonium hydroxide was
added. The resulting slurry (p~l 10-11) was diluted with 25
gallons of water and the solid was collected, rinsed with
water and dried ln _acu at 60C to give crude 5-bromo-6-
fluoro-2-methylquinoline (84.5% pure by gas chromatography
analysis). The material was recrystallized from hexane to
give 99.2~ pure 5-bromo-6-fluoro-2-methylquinoline.
EXAMPLE 4
Preparation of 2,5-Dimethy_-6-fluoro~uinoline
Under a nitrogen atmosphere, 24.0g (0.1 mole~ of
5-hromo-6-fluoro-2-methylquinoline, 2.~g (0.005 mole) of
dichloro[1,3-bisdiphenylphosphinopropanel nickel ~
catalyst, and 3~0 ml of diethyl ether were combined. 44 ml
of 3.17M methylmagnesium chloride in tetrahydrofuran was
added dropwise at a rapid rate. The reaction was allowed
to stir at room temperature overnight. q~he ether solution
was decanted off into 200 ml of 3N hyclrochloric acid in an
ice bath, accompanied by vigorous stirring. The aqueous
and organic layers were then separated. The aqueous layer
was extracted with 100 ml of ethyI acetate and cooled in an
ice bath, and the pH was adjusted to pH 10 with
concentrated ammonium hydroxide. This was extracted twice
with 100 ml of portions of ethyl acetate. The extracts
were combined and washed with 30 ml of brine, dried over
magnesium sulfate, and filtered and evaporatecl to give
14.9g of 2,5-dimethyl-6-fluoroquinoline of 94.4~ purity as
determined by gas chromatography an~lysis.
